Why ME/CFS Biomarker Headlines Keep Failing to Deliver
Every few years, headlines appear claiming that scientists have finally found a biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Each time, the community feels a surge of hope: maybe this is it—the long-awaited diagnostic test that will legitimize the disease and speed up treatment research.
And yet, decades later, we still don’t have a clinically validated biomarker. The latest announcement about the EpiSwitch blood test is just the newest chapter in this long story of excitement and disappointment.
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Why a Biomarker for ME/CFS Matters
A biomarker—a measurable biological signal that identifies a disease—could change everything for ME/CFS. It could shorten the years-long diagnostic delays, help distinguish ME/CFS from overlapping illnesses, and guide treatment development (Jason et al., 2023).
But identifying one has proven incredibly difficult. ME/CFS is a heterogeneous condition. No two patients are the same, and the biological pathways involved—immune, metabolic, vascular, and neurological—are deeply interconnected (Proal & VanElzakker, 2025).
The Pattern: Discovery, Hype, and Disappointment
The ME/CFS field has followed a predictable pattern for years:
A small study identifies a biological difference between patients and healthy controls.
The media declares it a “breakthrough blood test.”
The findings fail to replicate in larger, more diverse groups.
The discovery fades—until the next big claim.
This cycle has played out with cytokine panels (Montoya et al., 2017), mitochondrial enzyme assays (Armstrong et al., 2015), metabolomic signatures (Naviaux et al., 2016), and red blood cell deformability (Saha et al., 2019). Each produced intriguing findings, but none proved specific or stable enough to serve as a diagnostic test.
The Control Group Problem
A key reason biomarker research often collapses under scrutiny is who the patients are compared to. Most studies contrast ME/CFS patients with healthy controls only, not with people who have other fatiguing illnesses.
That means we can’t tell whether a biomarker is unique to ME/CFS—or just reflects chronic illness in general. For instance:
Ron Davis’s red blood cell deformability test found that cells from ME/CFS patients were less flexible (Saha et al., 2019). But red blood cell changes also occur in lupus, anemia, and other chronic diseases.
Cytokine studies show immune irregularities that overlap with depression and autoimmune disorders (Hornig et al., 2015).
Metabolic “hypometabolism” patterns could arise from many causes, including prolonged inactivity or inflammation (Naviaux et al., 2016).
Without disease controls—such as fibromyalgia, long-haul COVID / Post-Acute Sequelae of COVID (PASC), autoimmune fatigue, or multiple sclerosis—it’s impossible to prove that a biomarker truly belongs to ME/CFS.
The Latest Hype: EpiSwitch
The new EpiSwitch study, from Oxford Biodynamics, claims to have found a blood-based signature with up to 96 % accuracy for distinguishing ME/CFS from healthy individuals (Hunter et al., 2025). The test uses 3D genomic profiling to measure how DNA folds and regulates immune genes—an advanced “epigenetic” approach.
It’s an interesting concept, but again, the study is small, unreplicated, and lacks disease controls. We don’t know if this 3D genomic pattern is specific to ME/CFS or simply reflects a general state of chronic inflammation. Until independent researchers can reproduce the results in diverse patient groups, the EpiSwitch test remains a research tool, not a clinical diagnostic.
Why Single Biomarkers for ME/CFS Rarely Work
Given the complexity of ME/CFS, it’s unlikely that one molecule, one metabolite, or one genetic pattern will ever define the illness. Most experts now expect that a cluster—or panel—of biomarkers will be needed (Proal & VanElzakker, 2025). That could include:
Immune cell signaling markers
Metabolites reflecting mitochondrial dysfunction
Vascular or endothelial changes
Microbiome and gut-derived compounds
Epigenetic or transcriptional profiles
Such a multi-system approach fits what we know about ME/CFS: it’s not one simple disease, but a tangled web of immune and metabolic disruptions following infection or other stressors.
What Would Real Progress Look Like?
A true step forward in biomarker research would include:
Large, multi-center studies with hundreds of patients
Inclusion of disease controls, not just healthy ones
Transparent, open-data replication so others can test the findings
Validation across different severities (mild, moderate, severe)
Longitudinal tracking to see whether biomarkers change with symptom flares or recovery
Affordability and clinical feasibility for widespread testing
These are the benchmarks that separate a promising idea from a proven diagnostic.
Cautious Optimism Is Still Warranted
Despite the repeated disappointments, every biomarker study contributes valuable insight. Even if a finding doesn’t become a test, it helps map the biology of ME/CFS—its immune signatures, metabolic bottlenecks, and vascular abnormalities (Pretorius et al., 2025). Over time, these pieces may combine into a diagnostic panel that’s finally reliable and reproducible.
But for now, we should be skeptical of any claim that this time we’ve found the answer. True biomarkers require rigorous validation, not press releases.
Conclusion: Hope Without Hype
The search for a biomarker is one of the most important quests in ME/CFS research—but also one of the most misunderstood. Every few years, a new headline promises a breakthrough. What we really need is patient, rigorous science: replication, transparency, and large-scale collaboration. Until then, we can appreciate the progress without mistaking it for the finish line.
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Not yet. The EpiSwitch test is still in early stages and hasn’t been validated against other chronic conditions.
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Because ME/CFS research progresses in cycles—small studies, exciting results, then failed replication.
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They often include too few patients, lack disease controls, and use proprietary methods that can’t be independently tested.
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Probably not. ME/CFS will likely require a cluster of biomarkers representing the immune, metabolic, and vascular systems.
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Hope, but with healthy skepticism. Each discovery is a step forward, but a validated, specific biomarker is still years away.
References
Armstrong CW, McGregor NR, Butt HL, Gooley PR. Metabolism in chronic fatigue syndrome. Clin Ther. 2015;37(5):826-838.
Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015;1(1):e1400121.
Jason LA, Sunnquist M, Evans M, et al. Barriers to diagnosis and care in myalgic encephalomyelitis/chronic fatigue syndrome. Health Psychol Behav Med. 2023;11(1):2136502.
Montoya JG, Holmes TH, Anderson JG, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome. Proc Natl Acad Sci USA. 2017;114(34):E7150-E7158.
Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113(37):E5472-E5480.
Hunter E, Alshaker H, Bundock O, et al. Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling. J Transl Med. 2025;23(1):1048. Published 2025 Oct 8. doi:10.1186/s12967-025-07203-w
Pretorius E, Venter C, Kell DB, et al. Endothelial and microclot pathophysiology in ME/CFS and post-COVID conditions. Thromb Res. 2025;240:78-91.
Proal AD, VanElzakker MB. Pathogens accelerate features of human aging: a review of molecular mechanisms. Ageing Res Rev. 2025;102865.
Saha AK, Schmidt BM, Wilhelmy J, et al. Red blood cell deformability is diminished in patients with chronic fatigue syndrome. Biophys J. 2019;116(3):456-465.
